AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

作者：Setta Kaffetzi Niovi; Simpson Michael A; Navarini Alexander A; Patel Varsha M; Lu Hui Chun; Allen Michael H; Duckworth Michael; Bachelez Herve; Burden A David; Choon Siew Eng; Griffiths Christopher E M; Kirby Brian; Kolios Antonios; Seyger Marieke M B; Prins Christa; Smahi Asma; Trembath Richard C; Fratemali Franca; Smith Catherine H; Barker Jonathan N; Capon Francesca^*

来源：American Journal of Human Genetics, 2014, 94(5): 790-797.

DOI：10.1016/j.ajhg.2014.04.005

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit sigma 1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

• 出版日期2014-5-1